Molecular mechanisms of lifespan extension in long-lived mitocondrial superoxide dismutase sod-2 mutants
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PROVIDER: PRJNA1208437 | ENA |
REPOSITORIES: ENA
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Project description:To explore the molecular mechanisms of lifespan extension in sod-2 mutants in an unbiased manner, we used RNA sequencing to identify differentially expressed genes in sod-2 mutants compared to wild-type worms. We found a large number of gene expression changes at day 1 of adulthood and much fewer at day 8. Upregulated genes in sod-2 mutants included genes involved in innate immunity and cuticle development. There were many more differentially expressed genes between day 1 and day 8 of adulthood compared to differences between the genotypes.
2025-02-25 | GSE286219 | GEO
Project description:The importance of manganese superoxide dismutase (Mn-SOD), an evolutionarily ancient metalloenzyme maintaining the integrity and functions of mitochondria, was studied in oxidative stress treated Aspergillus fumigatus cultures. Deletion of the Mn-SOD gene (sodB) increased both the menadione sodium bisulfite (MSB) elicited oxidative stress, and the deferiprone (DFP) induced iron limitation stress sensitivity of the strain. Moreover, DFP treatment enhanced the MSB sensitivity of both the gene deletion mutant and the reference strain. Concurring with these results, RNS sequencing data also demonstrated that deletion of sodB largely altered the MSB induced oxidative stress response. The difference between the oxidative stress responses of the two strains manifested mainly in the intensity of the response. Importantly, upregulation of “Ribosome protein”, “Iron uptake”, and Fe-S cluster assembly” genes, alterations in the transcription of “Fe-S cluster protein” genes, downregulation of “Heme binding protein” genes under MSB stress were characteristic for only the DsodB gene deletion mutant. We assume that the elevated superoxide level generated by MSB treatment may have destroyed Fe-S cluster proteins of mitochondria in the absence of SodB mediated protection. Re-synthesis of Fe-S cluster proteins enhanced translation and increased iron demand changing iron metabolism and increasing DFP sensitivity considerably.
2025-01-01 | GSE269970 | GEO
Project description:Enterocyte Superoxide Dismutase 2 Deletion Drives Hyperinsulinemia and Obesity
| PRJNA664402 | ENA
Project description:A known human SNP in the matrix-binding domain of extracellular superoxide dismutase (EC-SOD), with an arginine to glycine substitution at position 213 (R213G), redistributes EC-SOD from the matrix into extracellular fluids. We reported that, following bleomycin (bleo), knock-in mice harboring the human R213G SNP (R213G mice), compared to wild-type (WT) littermates exhibit enhanced resolution of inflammation and protection against fibrosis. We tested the hypothesis that the EC-SOD R213G SNP promotes resolution via accelerated apoptosis of recruited alveolar macrophage (recAM).
2022-02-01 | GSE127345 | GEO
Project description:Purpose: Oxidative stress is a key contributor to the development of dysregulated inflammation in acute lung injury (ALI). A naturally occurring single nucleotide polymorphism in the key extracellular antioxidant enzyme, extracellular superoxide dismutase (EC-SOD), results in an arginine to glycine substitution (R213G) which promotes resolution of inflammation and protection against bleomycin-induced ALI. Previously we found that mice with the R213G mutation in EC-SOD have an inflammation-resolving transcriptomic profile at 7 days post-bleomycin However, the epigenetic differences between WT and R213G EC-SOD lungs have not been examined. Therefore, we used Next Generation microRNA (miR) Sequencing of lung tissue to identify dysregulated miRs 7 days after bleomycin in wild-type (WT) and R213G mice. Methods: WT and homozygous R213G EC-SOD (rs1799895) mice received one intratracheal administration of bleomycin in phosphate-buffered saline (PBS) (100 uL at 1 U/mL) or PBS at 8-12 weeks old. Lungs were harvested and frozen. Frozen lungs were homogenized, placed in Qiazol, and RNA was isolated using the miRNeasy Mini Kit (Qiagen). Samples underwent 1x150, directional, single-end sequencing using the Illumina hiSEQ 4000 system. Results: 1424 microRNAs were detected. Up/Down regulated microRNAs were defined as havinga FC > 1.2 and p <0.05. microRNAs "unique" to a genotype were defined as meeting the prevoius criteria in only one strain, or in both with a fold change 1.5x greater in one over the other. This method identified 92 WT and 235 R213G miRs uniquely dysregulated in their respective genotypes.
2020-05-29 | GSE147138 | GEO
Project description:In the heart, the serine carboxypeptidase cathepsin A (CatA) is distributed between lysosomes and the extracellular matrix (ECM). CatA-mediated degradation of extracellular peptides may contribute to ECM-remodeling and left ventricular (LV) dysfunction. This study aimed to evaluate the effects of CatA overexpression on LV remodeling. A proteomic analysis of the secretome of adult mouse cardiac fibroblasts upon digestion by CatA identified the extracellular antioxidant enzyme superoxide dismutase (EC-SOD) as a novel substrate of CatA (5-fold decreased abundance; p=0.0001). In vitro, cardiomyocytes and cardiac fibroblasts expressed and secreted CatA protein. EC-SOD protein was expressed and secreted only by cardiac fibroblasts. Cardiomyocyte-specific over-expression of CatA and increased activity in the LV of transgenic mice (CatA-TG) reduced EC-SOD protein levels by 43% (p<0.001). Loss of EC-SOD-mediated anti-oxidative protection resulted in accumulation of superoxide radicals (WT: 4.54±1.2 vs. CatA-TG: 8.62±2.3µmol/mg tissue/min; p=0.0012), increased inflammation, myocyte hypertrophy (WT: 19.8±1.0 vs. CatA-TG: 21.9±1.8µm; p=0.024), cellular apoptosis, and elevated mRNA expression of hypertrophy-related and pro-fibrotic marker genes, without effecting intracellular detoxifying proteins. In CatA-TG mice LV interstitial fibrosis formation was enhanced by 19% (p=0.028) and type I/type III collagen ratio was shifted towards higher abundance of collagen I fibers (p=0.026). Cardiac remodeling in CatA-TG was accompanied by increased LV weight/body weight and LV enddiastolic volume (WT: 50.8±5.8 vs. CatA-TG: 61.9±6.2 µl; p=0.018). Thus, in the heart CatA-mediated reduction of EC-SOD protein contributes to increased oxidative stress, myocyte hypertrophy, ECM remodeling and inflammation. This implicates CatA as a potential therapeutic target to prevent ventricular remodeling.
2020-07-10 | PXD019895 | Pride
Project description:Superoxide radical anion and other Reactive Oxygen Species are constantly produced during respiration. In mitochondria, the dismutation of the superoxide radical anion is accelerated by the mitochondrial superoxide dismutase 2 (SOD2), an enzyme that has been traditionally associated with antioxidant protection. However, increases in SOD2 expression promote oxidative stress, indicating that there may be a prooxidant role for SOD2. We show that SOD2, which normally binds manganese, can incorporate iron and generate an alternative isoform with peroxidase activity. The switch from manganese to iron allows FeSOD2 to utilize H2O2 to promote oxidative stress. We found that FeSOD2 is formed in cultured cells. FeSOD2 causes mitochondrial dysfunction and higher levels of oxidative stress in cultured cells. We show that formation of FeSOD2 converts an antioxidant defense into a prooxidant peroxidase that leads to cellular changes seen in multiple human diseases.
2017-12-05 | GSE106206 | GEO
Project description:We explored the in vitro activities of the dinuclear Mn2L2Ac and Mn2L2 complexes (where HL=2-{[di(2-pyridyl)- methylamino]-methyl}phenol), possessing dual superoxide dismutase(SOD) and catalase (CAT) activity, both individually and in conjunction with various Pt(II)-complexes, either as mixtures or as the Mn2-Pt adducts. Our findings revealed a notable up to 50% enhancement in the viability of healthy human breast cells, contrasted with a viability decrease as low as 50% in breast cancer cells upon combined treatments with Mn2 SOD mimics and Pt(II) complexes. Specifically, we synthesized and characterized the self-assembled Mn2-Pt adducts (isolated Mn2L2Pt and in situ Mn2L2Pt’), linking Mn2L2-core with the carboxylate group of PtDAPCl2 (dichloro(2,3-diaminopropionic acid) platinum(II)). The SOD activity of the isolated Mn2L2Pt adduct (kSOD=1.7×107 M-1 s-1) remained intact. We elucidated key mechanisms underlying the observed biological effects. We demonstrated that Mn2-containing formulations predominantly target mitochondrial processes, differently affecting the proteome of cancerous and healthy cells. They induced downregulation of H2S signaling and expression of mitochondrial complex I and III, as well as increased oxidative phosphorylation pathways and upregulation of EGFR in cancer cells. In contrast, healthy cells showed a decrease in EGFR expression and a moderate enrichment in oxidative phosphorylation pathways.
2024-08-28 | PXD051376 | Pride
Project description:Superoxide dismutase (EC 1.15.1.1) (SOD) is a standout amongst the most critical metal containing enzymes that can act as a main line of defense against oxidative stress. There has always been an increased interest globally to identify new plant sources with high SOD activity that are pharmacologically potent and have minimum side effects for their use as preventive medicine and in food industry. Trachyspermum ammi seeds showed high SOD activity and the enzyme was purified to homogeneity using various downstream processing techniques like; Salt precipitation, dialysis, IEX, Gel permeation, NATIVE- & SDS-PAGE.
2021-11-03 | PXD011955 | Pride
Project description:The oxidative stress theory of aging postulates that aging results from the accumulation of molecular damage caused by reactive oxygen species (ROS) generated during normal metabolism. Superoxide dismutases (SODs) counteract this process by detoxifying superoxide. It has previously been shown that elimination of either cytoplasmic or mitochondrial SOD in yeast, flies, and mice results in decreased lifespan. In this experiment, we examine the effect of eliminating each of the five individual sod genes present in Caenorhabditis elegans. In contrast to what is observed in other model organisms, none of the sod deletion mutants shows decreased lifespan compared to wild-type worms, despite a clear increase in sensitivity to paraquat- and juglone-induced oxidative stress. In fact, even mutants lacking combinations of two or three sod genes survive at least as long as wild-type worms. Examination of gene expression in these mutants reveals mild compensatory up-regulation of other sod genes. Interestingly, we find that sod-2 mutants are long-lived despite a significant increase in oxidatively damaged proteins. Testing the effect of sod-2 deletion on known pathways of lifespan extension reveals a clear interaction with genes that affect mitochondrial function: sod-2 deletion markedly increases lifespan in clk-1 worms while clearly decreasing the lifespan of isp-1 worms. Combined with the mitochondrial localization of SOD-2 and the fact that sod-2 mutant worms exhibit phenotypes that are characteristic of long-lived mitochondrial mutants-including slow development, low brood size, and slow defecation-this suggests that deletion of sod-2 extends lifespan through a similar mechanism. This conclusion is supported by our demonstration of decreased oxygen consumption in sod-2 mutant worms. Overall, we show that increased oxidative stress caused by deletion of sod genes does not result in decreased lifespan in C. elegans and that deletion of sod-2 extends worm lifespan by altering mitochondrial function.
| S-EPMC2628729 | biostudies-literature